HER3 (human epidermal growth factor receptor 3) belongs to the ErbB/HER subfamily of polypeptide growth factor receptors, which includes the epidermal growth factor (EGF) receptor (EGFR, ErbB1, HER1), the neu oncogene product (ErbB2, HER2), and the more recently identified ErbB3, HER3 and ErbB4, HER4 receptor proteins (see, e.g., Plowman et al. (1990), Proc. Natl. Acad. Sci. USA 87, 4905-4909; Hynes et. al. (1994) Biochim. Biophys. Acta Rev. Cancer 1198, 165-184). It is known that HER3 can bind multiple ligands, such as heregulin and the neuregulins 1 and 2; but that it lacks intrinsic tyrosine kinase activity (and because it is kinase inactive, the receptor can only initiate signal transduction when dimerized with another HER family member, such as HER1, HER2 or HER4).
More specifically, HER3 is a membrane-bound protein and has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell devision, proliferation, differentiation, migration and other cellular processes. Complex multilayered signaling generated receptor cross-talk and lateral signaling is becoming evident within the EGFR family and other receptor tyrosine kinases like MET (Engelmann et. al. (2007), Science 316, 1039-1043). Deregulated, aberrant signaling due to mutation, amplification and presence of active autrocrine loops may participate in development of cancer and other diseases. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors (see e.g. WO2008100624, WO2007077028, Horst et al. (2005) Int J Cancer, 115, 519-527; Xue et al. (2006) Cancer Res. 66, 1418-1426). HER3 is also known as LCCS2; ErbB-3; c-erbB3; erbB3-S; MDA-BF-1; MGC88033; c-erbB-3; p180-ErbB3; p45-sErbB3; p85-sErbB3; ERBB3.
When it comes to the role of HER3 in cancer, it has been suggested that HER3 may be necessary for HER2-mediated tumorigenesis, in the sense that HER2 may require HER3 in order to transform normal cells into cancer cells. For example, it has been found that increased expression of HER3 increases the signaling potency of HER2, whereas decreased HER3 expression results in the loss of HER2 activity. This has led to the hypothesis that HER3 may be involved in HER2-mediated tumorigenesis through dimerization with HER2.
It has also been suggested that HER3 may enable escape from inhibition of other HER receptors. For example, preclinical research has shown that upregulation of HER3 activity may be a mechanism by which tumor cells can escape tyrosine kinase inhibition of HER family receptors, and that tumor cells may compensate for tyrosine kinase inhibition of other HER receptors by increasing expression of HER3, which is kinase inactive. It has also been found that in HER2:HER3 heterodimers, HER2 transphosphorylates HER3.
HER3 has also been found to be overexpressed in several types of cancer (including without limitation breast and pancreatic cancer), and it has been found that there may be a correlation between the expression of HER2/HER3 and the progression from an non-invasive to an invasive stage (Baselga et al., 2009 Nature Reviews Cancer 9, 463-475).
Although, the role of HER3 in cancer and oncogenic signaling has been implicated (supra), its importance in an anti-cancer treatment remains unclear due to the complex ErbB network in which HER3 is a component thereof. Current immunotherapies primarily focus on inhibiting the action of HER2 and, in particular, heterodimerization of HER2/HER3 complexes (see, e.g., Sliwkowski et al. (1994) J. Biol. Chem. 269(20): 14661-14665).
It is an object of the present invention to provide improved immunotherapies that effectively inhibit HER3 signaling, and can be used to treat and diagnose a variety of cancers.